Germline BAP1 mutations predispose to malignant mesothelioma

• DOI: 10.1038/ng.912
• Publication Date: 2011-08-28T17:49:38Z
• Authors: Joseph R Testa; Mitchell Cheung; Jianming Pei; Jennifer E Below; Yinfei Tan; Eleonora Sementino; Nancy J Cox; A Umran Dogan; Harvey I Pass; Sandra Trusa; Mary Hesdorffer; Masaki Nasu; Amy Powers; Zeyana Rivera; Sabahattin Comertpay; Mika Tanji; Giovanni Gaudino; Haining Yang; Michele Carbone
• Keywords: Male; Mesothelioma; Uveal Neoplasms; Genetic Linkage; Pleural Neoplasms; Tumor Suppressor Proteins; Asbestos; Environmental Exposure; Article; Pedigree; 3. Good health; Risk Factors; Humans; Female; Genetic Predisposition to Disease; Melanoma; Ubiquitin Thiolesterase; Germ-Line Mutation

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.